A variety of growth factors that impact survival and development of oligodendrocyte (OLG) lineage cells in vivo and in culture may affect the extent of degeneration or remyelination of oligodendrocytes (OLGs) in white matter disease (Gao, Gillig et al. 2000; Mason, Suzuki et al. 2001; Armstrong, Le et al. 2002; Murtie, Zhou et al. 2005). Our results suggest that one of these molecules is brain derived neurotrophic factor (BDNF). Work in our lab during the previous funding period indicates that BDNF, through the mediation of trkB, influences proliferation and differentiation of OLG subpopulations in culture. In addition, BDNF +/- mice exhibit decreases in MBP+ myelin profiles and NG2+ progenitors that develop in the corpus callosum. Preliminary studies suggest that they also exhibit blunted increases in NG2+ cells and reduced numbers of MBP+ profiles in response to a cuprizone-elicited demyelinating lesion. Based on these results, we hypothesize that following a demyelinating lesion, BDNF, through the mediation of trkB, directly enhances OLG progenitor proliferation and differentiation, impacting OLG remyelination. In particular, we propose to 1) use BDNF +/- mice to examine the role of BDNF on proliferation and differentiation of OLG lineage cells in the cuprizone injury model. 2) use conditional knockout mice (TrkBCrePLPTE) that delete TrkB in proteoliplid (PLP)+ OLG lineage cells in response to tamoxifen to determine whether effects of BDNF in the cuprizone model are mediated directly by TrkB on OLG lineage cells and 3) investigate the therapeutic potential of BDNF by evaluating effects of exogenous BDNF on regenerating and damaged OLGs following a cuprizone lesion. These studies, designed to evaluate roles of BDNF in promoting survival and function of OLG lineage cells during and after a white matter lesion, will provide insights with which to optimize the repair of OLGs that deteriorate in white matter disease. This work may lead to the development of BDNF as a therapeutic agent. Moreover, it may lead to the identification of potential candidate genes for geneticists to test as susceptibility loci for these devastating diseases.